The preparation and use of 6-aryluracils is known. For example, the following references are known: Johnson et al., "Researches on Pyrimidines LXXIV. Synthesis of 4-Phenylcytosine," J. Am. Chem. Soc., Vol. 37, pp. 378-383 (1915); Gershon et al. "Pyrimidines. III. Some 6-Substituted Di- and Trichloropyrimidines," J. Med. Chem., vol. 6, pp. 87-89 (Jan., 1963); Moszew et al., "New Type of Addition of Aromatic Isocyanates to Benzoylacetamide. 1,6-Diaryl Derivatives of Uracil," Zesz. Nauk. Univ. Jagiellon., Pr. Chem. 1969, No. 14, pp. 31-45, C.A. 72:12242e; and Lacey, "Derivatives of Acetoacetic Acid. Parts V and VI.", J. Chem. Soc., pp. 839-849 (1954). Of these references Gershon et al. and Lacey disclose only anticancer use for related compounds.
Clark et al., "Heterocyclic Studies. Part XIX. Some 6-(Substituted phenyl)-uracil and -thiouracil Derivatives, J. Chem. Soc. (C)., pp. 1945-8 (1971) and Clark et al., "Heterocyclic Studies. Part XXVII. Mass Spectra of 6-(meta- and para-Substituted-phenyl)-uracil and -thiouracil Derivatives", J. Chem. Soc., Perkin II, pp. 233-7 (1972) both teach treatment of hyperthyroidism. Specifically, Clark et al., (1972) discloses that 6-phenyluracil and its p-nitrophenyl analog are thymidine phosphorylase enzyme inhibitors.
Additionally, U.S. Pat. No. 4,171,429 discloses only antiviral and antileukemic activity for various uracils including uracils having 6-aryl substituents. A wide variety of 6-aryl uracils are disclosed in German Offenlegungsschrift Pat. No. 2,142,317 but the only utilities taught for the named compounds are as hypnotic and narcotic agents.
Corresponding dihydrouracils are prepared by reduction of N-blocked uracils in a reaction analogous to that disclosed by Hannon et al., Tetrahedron Letters, 21, 1105 (1980).
On the other hand, analgetic, antipyretic and antiinflammatory effects are taught for 1,3-disubstituted 6-methyluracils by Senda et al., "Pyrimidine Derivatives and Related Compounds. 15. Synthesis and Analgetic and Antiinflammatory Activities of 1,3-Substituted 5-Amino-6-Methyluracil Derivatives." J. Med. Chem., vol. 15, No. 5, pp. 471-6 (1972).
Ahmed et al. "Purines, Pyrimidines, and Imidazoles. Part XLIV. Synthesis of Some Dihydro-1,3-oxazine Derivatives and Related Substituted Uracils," J.C.S. Perkin I, pp. 1969-75 (1976) discloses a 2-imino-6-methyl-1,3-oxazine derivative analogous to compounds denoted as III herein, but does not teach the novel 6-substituted intermediates II defined hereinafter as the present invention. Ahmed et al. processes for preparing uracils are limited to reactions of beta-keto esters with N,N-dialkyl urea, thus failing to teach the use of the acid addition salt of S-alkylisothiourea VI which provided the unexpected invention process shown hereinafter. In fact, contrary to the present invention Ahmed et al. reiterates the teaching of Lacey that a beta-keto ester can not replace diketene in a reaction with various urea derivatives to produce aryl derivatives of 1,3-oxazine. The alternatives suggested by Ahmed et al. do not alter Lacey's teaching. In other words, the novel intermediates of the present invention are not made obvious by the references.
Finally, Japanese patent application number J5 7035-515 by Sankyo (denoted hereafter as I) discloses an oxazine derivative having the formula VII teaching immunoregulatory, fungicidal or analgesic activity. Further J4 7017781 also by Sankyo (denoted hereafter as II) having as an abstract Derwent 62348T-BC discloses a preparation of the oxazine derivative by a process which is not related to the chemical process of the present case. In fact, the compound of formula III can not be prepared by the method taught in Sankyo II. Therefore, Sankyo I and II cannot be said to teach the present invention since neither reference discloses a process which can be used to make the present novel intermediate, nor teaches that 6-aryluracils of the present invention are antiarthritic or antiinflammatory agents.
Thus, none of the above references teach the present novel processes or their novel intermediates for preparing selected 6-aryluracils. Further, the unexpected activity for either antiinflammatory or antiarthritic use of the 6-aryluracils as now taught by the present invention is not taught by the noted references.
Belgian Patent No. 882,315 discloses the preparation and various uses of 6-aryl pyrimidinones including interferon induction, antiviral and immunoregulatory activity. Further, copending U.S. application Ser. No. 303,694 teaches antiarthritic activity for selected compounds within the scope of the Belgian patent.
However, again uses for 6-aryluracils novel intermediates and processes for making selected 6-aryluracils using the novel intermediates of the present invention are not made obvious by either the Belgian Patent or the U.S. application. Particularly, the mechanism of action for the instant use of 6-aryluracils is not understood. For example, 6-aryluracils do not produce neutropenia and agranulocytosis which is indicative of immunosuppressant activity. Further, lymphopenia analogous to corticoid activity is not induced by 6-aryluracils. A functional adrenal gland is not required for 6-aryluracils activity indicating the activity is not dependent on corticosteroid production. Finally, the present 6-aryluracils are clearly different from the related 2-amino-6-arylpyrimidinones of the above noted U.S. application Ser. No. 303,694 because uracils do not induce interferon.